Ectopic Lipids in the Pancreatic Alpha Cells Link Insulin Resistance to Hyperglycemia Just as insulin insufficiency can lead to elevated glucagon secretion, preliminary data suggest that impaired insulin action within the ?-cell can also promote hyperglucagonemia, hyperglycemia, aberrant gluconeogenesis, and excess glucose efflux from the liver. Pancreatic perfusion with anti-insulin serum causes marked hyperglucagonemia, and ablation of insulin receptor from ?-cells prompts fed hyperglucagonemia and glucose intolerance. Sphingolipids, such as ceramides and glucosylceramides, are an important class of bioactive lipids which may impair insulin signal transduction in the ?-cell. Most recently, it has been demonstrated that ceramide is sufficient to impair insulin-induced suppression of glucagon from ?-cells. The levels of these lipids change as a function of adipose tissue mass and functionality, and are partially driven by cellular availability of palmitoyl-CoA. Aberrant accumulation of sphingolipids has been implicated in a multitude of metabolic processes, including atherosclerosis, insulin resistance, lipotoxic heart failure, ?-cell apoptosis and ?-cell dysfunction. The adipose-derived secretory factor adiponectin promotes an increase in ceramide catabolism, which is dependent on adiponectin receptors 1 and 2 (AdipoR1/R2). The associated ceramidase activity promotes ceramide degradation and correlates with the suppression of hepatic glucose efflux. Fibroblast growth factor 21 (FGF21, a reported glucagon suppressor), rapidly stimulates adiponectin secretion and improves glycemia by harnessing adiponectin?s ceramide-lowering potential. Preliminary results suggest that novel small molecule mimetics of adiponectin (currently in pharmaceutical development) may offer the same potential therapeutic benefits of adiponectin to improve glucose homeostasis by decreasing ceramide excess and glucagon secretion. We hypothesize that: 1) Preventing ceramide excess within ?-cells enhances suppression of glucagon by 3 of its endogenous attenuating signals (insulin, leptin, and GABA-all repress glucagon via Akt/FoxO1) A portion of adiponectin?s glucose-lowering effects are mediated by inhibiting glucagon secretion which is directly triggered by adiponectin receptor-driven lowering of sphingolipids in ?-cells; 3) The glucagon-suppressive effects of FGF21 are mediated by ceramide-lowering within the ?-cell in an adiponectin-dependent manner; and 4) Limiting glucagon secretion or glucagon receptor activation improves insulin signal transduction by preventing glucagon-induced activation of PP2A. In essence, we believe that the insulin-desensitizing effects heavily studied in muscle, liver and adipose can also occur in the ?-cell, triggering hyperglucagonemia, hyperglycemia, and metabolic sequelae of diabetes. As such, many potential therapeutic agents currently under development (including FGF21 analogs, adiponectin mimetics, and ceramide synthesis inhibitors) may function as glucagon suppressors via sphingolipid-mediated actions and may require glucagon-suppressive actions in order to achieve full anti-diabetic efficacy. Newly-available imaging mass spectrometry techniques make these studies feasible for the first time.